PROJECT SUMMARY: Neurodegenerative diseases are characterized by CNS accumulations of misfolded protein aggregates that define the neuropathology of each disorder, including frontotemporal dementia (FTD) or frontotemporal lobar degeneration (FTLD), the second most common cause of dementia in patients under the age of 65. There have been dramatic advances in research on FTLD that have revolutionized concepts about FTLD since this Program Project Grant (PPG) was renewed in 2005. Thus, tau, TDP-43 or FUS inclusions now are recognized as the defining CNS lesions in ~45%, ~50% and ~5% of FTLD, respectively, and these FTLD variants are designated FTLD-Tau, FTLD-TDP and FTLD-FUS, respectively. FTD may be sporadic or familial, and hereditary FTD with parkinsonism linked to chromosome 17q21-22 is caused by >30 M>APT mutations while >30 TARDBP and FUS mutations were discovered in the last 3 years that associate with amyotrophic lateral sclerosis (ALS), but TARDBP mutations also associate with FTLD plus ALS. Notably, although FTLD-Tau, FTLD-TDP and FTLD-FUS account for nearly all FTLD cases, Alzheimer's disease (AD) is the cause of FTD in ~25% of patients. Moreover, TDP-43 pathology co-occurs in 30-50% of patients with AD, Parkinson's disease and dementia with Lewy bodies. Given the heterogeneity of FTD and the clinical overlap of FTD with AD and other disorders, a thorough postmortem examination of FTD patients followed in Clinical Core of this PPG is essential to define the clinicopathologic phenotypes of FTD and link them to genetic, imaging and biomarker findings as well as to provide CNS samples for research. Further, the collection of biofluids is essential to identify FTD biomarkers for the early and reliable diagnosis of FTD. Accordingly, Core D acquires, characterizes, banks, distributes and studies CNS and biofluid samples from FTD patients and control subjects followed in the Clinical Core of this PPG.